Cardiovascular diseases are the leading cause of death worldwide. Heart failure can develop from a variety of pathological conditions, such as diseases, including but not limited to, hypertension, atherosclerosis, viral infections, cardiotoxic pharmacological agents, hypertrophy, and others, and/or injuries, such as including but not limited to, trauma, surgery, and others. Although such heart diseases and injuries may be caused by different etiological factors, once initiated, the general pattern of pathological progression of the diseases and/or injuries have similarities, such as the following illustrative sequence of events: (1) detrimental conditions or factors (2) cardiomyocyte insults or injuries (3) cardiomyocyte apoptosis and/or necrosis (4) cardiomyocyte death/dropout (5) recruitment of fibroblasts (6) increase of extracellular matrix deposition (7) cardiac fibrosis (8) possible impairment of cardiac contractile function (9) potential heart failure.
Fibrosis is characterized by a loss of normal tissue architecture and replacement with scar tissue. Either or both of those conditions may lead to organ failure. Fibrosis involves a multitude of cellular responses, one of which is the extracellular matrix deposition of collagen. Without being bound by theory, it is believed herein that fibroblasts play a primary role in the extracellular matrix deposition of collagen. It is further believed herein that cell apoptosis and/or cell necrosis leads to the recruitment of fibroblasts to the dead or dying cell, ultimately resulting in fibrosis. Without being bound by theory, it is believed herein that directly or indirectly decreasing, slowing, or preventing cardiac cells such as cardiomyocytes from undergoing apoptosis and/or necrosis may either slow or preclude the progression of diseased heart to heart failure, leading to a therapeutic benefit. In addition, though without being bound by theory, it is believed herein that directly or indirectly decreasing, slowing, or preventing excessive extracellular matrix deposition, such as from cardiac fibroblasts may also either slow or preclude the progression of diseased heart to heart failure, leading to a therapeutic benefit.
Currently, there are no known effective ways to reduce or reverse cardiac fibrosis. For example, though the use of β-blockers and angiotension-converting enzyme (ACE) inhibitors are used in the clinic, and can improve cardiac function, such a treatment has been reported to have a limited effect in preventing apoptosis or necrosis. Further, the efficacy of those drugs to reduce cardiac fibrosis has also been reported to be limited.
It has been discovered herein that bone morphogenetic proteins, such as BMPs-10, are potent cytokines having the capability of inhibiting cell apoptosis and/or necrosis, such as cardiomyocyte apoptosis and/or necrosis. It has also been discovered herein that BMPs-10 are potent cytokines having the capability of inhibiting extracellular matrix deposition by cardiac fibroblasts. It is appreciated herein that the dual activity of the bone morphogenetic proteins discovered herein may be useful in treating heart disease by a potential plurality of mechanisms, including directly inhibiting cardiac cell death, indirectly inhibiting fibrosis by inhibiting cardiac cell death, and/or directly inhibiting fibrosis.
In one illustrative embodiment of the invention, uses of a composition in the manufacture of a medicament for treating a heart disease or a heart injury, or a combination thereof, is described. In one illustrative aspect, the composition includes a therapeutically effective amount of a BMP-10, or alternatively one or more BMPs-10. In another embodiment, the composition also includes one or more carriers, diluents, and/or excipients.
In another illustrative embodiment, compositions are described herein for treating a heart disease or a heart injury, or a combination thereof. In one aspect, the compositions include a therapeutically effective amount of a BMP-10, or alternatively one or more BMPs-10.
In another illustrative embodiment, methods are described herein for treating a heart disease or a heart injury, or a combination thereof. In one aspect, the methods include the step of administering a composition comprising a therapeutically effective amount of a BMP-10, or alternatively one or more BMPs-10.
In another illustrative embodiment, pharmaceutical compositions are described herein. In one aspect, the compositions include a therapeutically effective amount of a BMP-10, or alternatively one or more BMPs-10, for treating a heart disease or a heart injury, or a combination thereof.